Suppressing effect of CMPPE, a new positive allosteric modulator of the GABAB receptor, on alcohol self-administration and reinstatement of alcohol seeking in rats

Paola Maccioni; Federica Fara; Irene Lorrai; Carla Acciaro; Claudia Mugnaini; Federico Corelli; Giancarlo Colombo

doi:10.1016/j.alcohol.2018.05.015

Suppressing effect of CMPPE, a new positive allosteric modulator of the GABA_B receptor, on alcohol self-administration and reinstatement of alcohol seeking in rats

Alcohol. 2019 Mar:75:79-87. doi: 10.1016/j.alcohol.2018.05.015. Epub 2018 May 31.

Authors

Paola Maccioni¹, Federica Fara¹, Irene Lorrai², Carla Acciaro¹, Claudia Mugnaini³, Federico Corelli³, Giancarlo Colombo⁴

Affiliations

¹ Neuroscience Institute, Section of Cagliari, National Research Council of Italy, I-09042 Monserrato, CA, Italy.
² Neuroscience Institute, Section of Cagliari, National Research Council of Italy, I-09042 Monserrato, CA, Italy; Department of Biomedical Sciences, University of Cagliari, I-09042 Monserrato, CA, Italy.
³ Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, I-53100 Siena, SI, Italy.
⁴ Neuroscience Institute, Section of Cagliari, National Research Council of Italy, I-09042 Monserrato, CA, Italy. Electronic address: colomb@unica.it.

PMID: 30468987
DOI: 10.1016/j.alcohol.2018.05.015

Abstract

Positive allosteric modulators (PAMs) of the GABA_B receptor constitute a class of pharmacological agents gaining increasing attention in the alcohol research field because of their ability to suppress several alcohol-related behaviors in rodents. CMPPE is a novel GABA_B PAM, still limitedly characterized in vivo. It was therefore of interest to test its ability to affect operant, oral self-administration of alcohol and cue-induced reinstatement of alcohol seeking in alcohol-preferring rats. To this end, female Sardinian alcohol-preferring (sP) rats were trained to lever-respond for alcohol (15% v/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding had stabilized, rats were exposed to test sessions (under the FR5 [Experiment 1] and progressive ratio [PR; Experiment 2] schedules of reinforcement) preceded by treatment with CMPPE (0, 2.5, 5, and 10 mg/kg; intraperitoneally [i.p.]). In Experiment 3, once lever-responding had stabilized, rats underwent an extinction responding phase and then a single reinstatement session during which lever-responding was resumed by the non-contingent presentation of a complex of alcohol-associated cues; CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) was administered before the reinstatement session. Selectivity of CMPPE action was assessed by evaluating the effect of CMPPE (0, 2.5, 5, and 10 mg/kg; i.p.) on self-administration of a chocolate solution in male Wistar rats (Experiment 4). In Experiments 1 and 2, treatment with 5 and 10 mg/kg CMPPE reduced lever-responding and breakpoint for alcohol. In Experiment 3, treatment with 5 and 10 mg/kg CMPPE suppressed reinstatement of alcohol seeking. In Experiment 4, no dose of CMPPE affected lever-responding for the chocolate solution. These results extend to CMPPE the ability of all previously tested GABA_B PAMs to affect alcohol-motivated behaviors in rodents and confirm that these effects are a shared feature of the entire class of GABA_B PAMs. This conclusion is of relevance in view of the forthcoming transition of GABA_B PAMs to clinical testing.

Keywords: Alcohol self-administration; CMPPE; GABA(B) receptor; Positive allosteric modulator; Rat.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alcohol Drinking / prevention & control*
Alcohol Drinking / psychology
Allosteric Regulation / drug effects
Allosteric Regulation / physiology
Animals
Dose-Response Relationship, Drug
Ethanol / administration & dosage*
Female
GABA Modulators / therapeutic use*
GABA-B Receptor Agonists / therapeutic use*
Male
Pyrazoles / therapeutic use*
Pyrimidines / therapeutic use*
Rats
Rats, Wistar
Receptors, GABA-B / physiology*
Self Administration
Treatment Outcome

Substances

2-(1-(2-(4-chlorophenyl)-5-methylpyrazolo(1,5-a)pyrimidin-7-yl)-2-piperidinyl)ethanol
GABA Modulators
GABA-B Receptor Agonists
Pyrazoles
Pyrimidines
Receptors, GABA-B
Ethanol